Pancreatic cholesterol esterase (CEase) is a lipolytic enzyme that catalyzes the hydrolysis of cholesteryl esters, phospholipids and triacylglycerols in the intestinal tract. The enzyme may play a role in the absorption of dietary cholesterol across the intestinal mucosa and eventually into the bloodstream, though certain literature teaches away from this physiological role, Watt and Simmons, J. Lipid Res., 22, 157-165 (1981). Given the legendary connection between blood serum cholesterol levels and atherosclerosis, it is reasonable to suspect that reagents that specifically and rapidly inhibit CEase may be worthy of investigation for use in the prophylaxis and/or treatment of the disease. Such agents would be of enormous benefit to the United States and other industrialized societies where atherosclerosis is one of the most prominent causes of death. For example, nearly half of the yearly mortality in the United States results from arteriosclerosis and its sequelae, such as heart attack, stroke, etc. Moreover, the cost to society for surgical and pharmacological management of the disease as well as lost productivity is staggering. It can therefore be seen that there is a continuing, serious and immediate need for development of means of reducing the risk for arteriosclerosis.
One of the often discussed techniques is dietary control. Of course, if diet intake is controlled to reduce the intake of fats, particularly saturated fats, it necessarily follows that the quantity of these materials as absorbed into the blood stream will be decreased. However, such dietary control has proven difficult in modern Western society. Particularly this is true in the United States, where foods are overwhelmingly high in fat content. Thus, for example, in the United States it is generally recognized that high blood cholesterol concentrations provide a significant risk factor in heart disease. It is also generally recognized that the high risk factor for heart disease in the Western world, and particularly the United States is caused by eating foods high in saturated fats, such as many red meats. Accordingly, there is a very real and continuing interest in decreasing either the intake of food substances that have high cholesterol content, or correspondingly in some manner decreasing the absorption rate of the cholesterol and fats through the alimentary tract.
Moreover, since CEase is required for the absorption of dietary fatty acids into the bloodstream, CEase inhibitors may serve as hypocaloric agents (i.e. blockers of the absorption of dietary calories as fat). Such a treatment would be useful in the treatment of obesity, a health problem that afflicts one-third of Americans. It is also a known risk factor in diabetes, atherosclerosis and other life threatening diseases.
It can therefore be seen that there is a real problem, with regard to control of dietary cholesterol. The huge amounts of data documenting the problem suggests the critical need for research and efforts at solving it. There are three possible approaches to lowering blood cholesterol levels for prevention and/or treatment of atherosclerosis: (a) removal of cholesterol from the body; (b) inhibition of de novo cholesterol biosynthesis; (c) prevention of absorption of dietary cholesterol. The first two approaches have been used commercially with some degree of success. For example, the drug Questran.RTM., which contains the cationic resin cholestyramine, is marketed by Bristol-Myers and lowers blood cholesterol by binding to bile salts in the intestinal lumen. The complex of Questran.RTM. and bile salts is eliminated in the feces, and the liver responds to the loss of bile salts by increasing receptor-mediated uptake of cholesterol ester-rich lipoproteins from the bloodstream. In 1988 Merck, Sharp and Dohme began marketing the HMG-CoA reductase inhibitor Mevacor.RTM., which prevents cholesterol biosynthesis in the liver. While these efforts are steps along the way, there remains a continuing need for further treatments and approaches.
The third approach, i.e., prevention of absorption of dietary cholesterol, has been largely unexploited as a pharmacological method for treatment of atherosclerosis. One way of prevention of absorption of dietary cholesterol is to cover the walls of the intestinal tract with something which prevents absorption of dietary cholesterol through the intestinal mucosa. This, however, is difficult and not practical because it inhibits the normal digestive process. A far more effective approach would be to develop CEase inhibitors with demonstrated capability of blocking cholesterol absorption. These inhibitors could then be introduced into the alimentary tract through appropriate delivery systems where it would then function to block cholesterol absorption. This invention is predicated upon the discovery of certain novel CEase inhibitors to successfully block cholesterol absorption, to their use for decreasing the absorption of dietary cholesterol and other fats, and to a pharmaceutical composition comprising the active compound in unit dosage formulations.